The Use of High Quality Chemical Tools to Rescue TBK1 Function and Identify Novel ATP-Competitive Targets in ALS
Abstract
We are developing chemical tools and biological reagents to interrogate the regulation of kinase-mediated biological pathways as new avenues to reduce the accumulation of toxic protein aggregates in ALS. TDP-43 is the most commonly misfolded and deposited protein in ALS. Failure of the autophagy system is one mechanism that allows proteins like TDP-43 to accrue in aggregates. TBK1 is a human protein kinase that plays an essential role in autophagy and which, through multiple genetic studies, has been confirmed as a protein that exhibits inactivating mutations in ALS patients. We have identified linkable compounds that potently engage TBK1 in cells and several putative TRAF3-recruiting ligands.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2023
- Accession Number
- AD1214740
Entities
People
- Alison D Axtman
- Andreas Kramer
- Carrow I. Wells
- David Drewry
- Filiz Senbabaoglu
- Frances M. Bashore
- James E. Dunford
- Jeffery L. Smith
- Mohammad A. Hossain
- Stefanie Howell
- Tammy M Havener
- Thomas M. Durcan
- Udo Oppermann
- Zachary W. Davis-gilbert
Organizations
- McGill University
- University of North Carolina at Chapel Hill